Approaches to identify extracellular receptor–ligand interactions

• Recombinant proteins can be used for large scale receptor interaction screening. • Cell-based assays permit study of receptor interactions in context of the membrane. • Cell-based genome-scale genetic screens identify pathways for ligand recognition. Thousands of secreted factors and plasma membrane-associated cell surface receptors are categorised into families that vary widely in their structures and functions. They often participate in extracellular binding events, but due to their unique physicochemical properties, their interactions are challenging to study. As lists of extracellular proteins become more complete and accurate, new methodologies are being developed to systematically identify how these proteins interact. Two main approaches have been used: direct binding between recombinant soluble receptor ectodomains and cell-based assays. Recent advances in chemoproteomic reagents, cDNA overexpression, and cell-based genetic approaches promote the identification of extracellular protein–protein interactions within the context of an intact plasma membrane in living cells and opens up the discovery of cell surface recognition events that were previously intractable.